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Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%. Patients and methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes. Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival. Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2–49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9–9.5; 599 events) and 17.2 months (95% CI 15.3–22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effe

Coastal ecosystems are highly complex and driven by multiple environmental factors. To date we lack scientific evidence for the relative contribution of natural and anthropogenic drivers for the majority of marine habitats in order to adequately assess the role of different stressors across the European seas. Such relationship can be investigated by analysing the correlation between environmental variables and biotic patterns in multivariate space and taking into account non-linearities. Within the framework of the EMBOS (European Marine Biodiversity Observatory System) programme, hard bottom intertidal communities were sampled in a standardized way across European seas. Links between key natural and anthropogenic drivers and hard bottom communities were analysed using Boosted Regression Trees modelling. The study identified strong interregional variability and showed that patterns of hard bottom macroalgal and invertebrate communities were primarily a function of tidal regime, nutrient loading and water temperature (anomalies). The strength and shape of functional form relationships varied widely however among types of organisms (understorey algae composing mostly filamentous species, canopy-forming algae or sessile invertebrates) and aggregated community variables (cover or richness). Tidal regime significantly modulated the effect of nutrient load on the cover and richness of understorey algae and sessile invertebrates. In contrast, hydroclimate was more important for canopy algae and temperature anomalies and hydroclimate separately or interactively contributed to the observed patterns. The analyses also suggested that climate-induced shifts in weather patterns may result in the loss of algal richness and thereby in the loss of functional diversity in European hard bottom intertidal areas.

In the frame of the COST ACTION ‘EMBOS’ (Development and implementation of a pan-European Marine Biodiversity Observatory System), coverage of intertidal macroalgae was estimated at a range of marine stations along the European coastline (Subarctic, Baltic, Atlantic, Mediterranean). Based on these data, we tested whether patterns in macroalgal diversity and distribution along European intertidal rocky shores could be explained by a set of meteo-oceanographic variables. The variables considered were salinity, sea surface temperature, photosynthetically active radiation, significant wave height and tidal range and were compiled from three different sources: remote sensing, reanalysis technique and in situ measurement. These variables were parameterized to represent average conditions (mean values), variability (standard deviation) and extreme events (minimum and maximum values). The results obtained in this study contribute to reinforce the EMBOS network approach and highlight the necessity of considering meteo-oceanographic variables in long-term assessments. The broad spatial distribution of pilot sites has allowed identification of latitudinal and longitudinal gradients manifested through species composition, diversity and dominance structure of intertidal macroalgae. These patterns follow a latitudinal gradient mainly explained by sea surface temperature, but also by photosynthetically active radiation, salinity and tidal range. Additionally, a longitudinal gradient was also detected and could be linked to wave height.

Examining how variability in population abundance and distribution is allotted among different spatial scales can inform of processes that are likely to generate that variability. Results of studies dealing with scale issues in marine benthic communities suggest that variability is concentrated at small spatial scales (from tens of centimetres to few metres) and that spatial patterns of variation are consistent across ecosystems characterized by contrasting physical and biotic conditions, but this has not been formally tested. Here we quantified the variability in the distribution of intertidal rocky shore communities at a range of spatial scales, from tens of centimetres to thousands of kilometres, both in the NE Atlantic and the Mediterranean, and tested whether the observed patterns differed between the two basins. We focused on canopy-forming macroalgae and associated understorey assemblages in the low intertidal, and on the distribution of Patella limpets at mid intertidal levels. Our results highlight that patterns of spatial variation, at each scale investigated, were consistent between the Atlantic and the Mediterranean, suggesting that similar ecological processes operate in these regions. In contrast with former studies, variability in canopy cover, species richness and limpet abundance was equally distributed among spatial scales, possibly reflecting the fingerprint of multiple processes. Variability in community structure of low intertidal assemblages, instead, peaked at the largest scale, suggesting that oceanographic processes and climatic gradients may be important. We conclude that formal comparisons of variability across scales nested in contrasting systems are needed, before any generalization on patterns and processes can be made.

Within the COST action EMBOS (European Marine Biodiversity Observatory System) the degree and variation of the diversity and densities of soft-bottom communities from the lower intertidal or the shallow subtidal was measured at 28 marine sites along the European coastline (Baltic, Atlantic, Mediterranean) using jointly agreed and harmonized protocols, tools and indicators. The hypothesis tested was that the diversity for all taxonomic groups would decrease with increasing latitude. The EMBOS system delivered accurate and comparable data on the diversity and densities of the soft sediment macrozoobenthic community over a large-scale gradient along the European coastline. In contrast to general biogeographic theory, species diversity showed no linear relationship with latitude, yet a bell-shaped relation was found. The diversity and densities of benthos were mostly positively correlated with environmental factors such as temperature, salinity, mud and organic matter content in sediment, or wave height, and related with location characteristics such as system type (lagoons, estuaries, open coast) or stratum (intertidal, subtidal). For some relationships, a maximum (e.g. temperature from 15–20°C; mud content of sediment around 40%) or bimodal curve (e.g. salinity) was found. In lagoons the densities were twice higher than in other locations, and at open coasts the diversity was much lower than in other locations. We conclude that latitudinal trends and regional differences in diversity and densities are strongly influenced by, i.e. merely the result of, particular sets and ranges of environmental factors and location characteristics specific to certain areas, such as the Baltic, with typical salinity clines (favouring insects) and the Mediterranean, with higher temperatures (favouring crustaceans). Therefore, eventual trends with latitude are primarily indirect and so can be overcome by local variation of environmental factors.

Coastal ecosystems are highly complex and driven by multiple environmental factors. To date we lack scientific evidence for the relative contribution of natural and anthropogenic drivers for the majority of marine habitats in order to adequately assess the role of different stressors across the European seas. Such relationship can be investigated by analysing the correlation between environmental variables and biotic patterns in multivariate space and taking into account non-linearities. Within the framework of the EMBOS (European Marine Biodiversity Observatory System) programme, hard bottom intertidal communities were sampled in a standardized way across European seas. Links between key natural and anthropogenic drivers and hard bottom communities were analysed using Boosted Regression Trees modelling. The study identified strong interregional variability and showed that patterns of hard bottom macroalgal and invertebrate communities were primarily a function of tidal regime, nutrient loading and water temperature (anomalies). The strength and shape of functional form relationships varied widely however among types of organisms (understorey algae composing mostly filamentous species, canopy-forming algae or sessile invertebrates) and aggregated community variables (cover or richness). Tidal regime significantly modulated the effect of nutrient load on the cover and richness of understorey algae and sessile invertebrates. In contrast, hydroclimate was more important for canopy algae and temperature anomalies and hydroclimate separately or interactively contributed to the observed patterns. The analyses also suggested that climate-induced shifts in weather patterns may result in the loss of algal richness and thereby in the loss of functional diversity in European hard bottom intertidal areas.

In the frame of the COST ACTION ‘EMBOS’ (Development and implementation of a pan-European Marine Biodiversity Observatory System), coverage of intertidal macroalgae was estimated at a range of marine stations along the European coastline (Subarctic, Baltic, Atlantic, Mediterranean). Based on these data, we tested whether patterns in macroalgal diversity and distribution along European intertidal rocky shores could be explained by a set of meteo-oceanographic variables. The variables considered were salinity, sea surface temperature, photosynthetically active radiation, significant wave height and tidal range and were compiled from three different sources: remote sensing, reanalysis technique and in situ measurement. These variables were parameterized to represent average conditions (mean values), variability (standard deviation) and extreme events (minimum and maximum values). The results obtained in this study contribute to reinforce the EMBOS network approach and highlight the necessity of considering meteo-oceanographic variables in long-term assessments. The broad spatial distribution of pilot sites has allowed identification of latitudinal and longitudinal gradients manifested through species composition, diversity and dominance structure of intertidal macroalgae. These patterns follow a latitudinal gradient mainly explained by sea surface temperature, but also by photosynthetically active radiation, salinity and tidal range. Additionally, a longitudinal gradient was also detected and could be linked to wave height.

Examining how variability in population abundance and distribution is allotted among different spatial scales can inform of processes that are likely to generate that variability. Results of studies dealing with scale issues in marine benthic communities suggest that variability is concentrated at small spatial scales (from tens of centimetres to few metres) and that spatial patterns of variation are consistent across ecosystems characterized by contrasting physical and biotic conditions, but this has not been formally tested. Here we quantified the variability in the distribution of intertidal rocky shore communities at a range of spatial scales, from tens of centimetres to thousands of kilometres, both in the NE Atlantic and the Mediterranean, and tested whether the observed patterns differed between the two basins. We focused on canopy-forming macroalgae and associated understorey assemblages in the low intertidal, and on the distribution of Patella limpets at mid intertidal levels. Our results highlight that patterns of spatial variation, at each scale investigated, were consistent between the Atlantic and the Mediterranean, suggesting that similar ecological processes operate in these regions. In contrast with former studies, variability in canopy cover, species richness and limpet abundance was equally distributed among spatial scales, possibly reflecting the fingerprint of multiple processes. Variability in community structure of low intertidal assemblages, instead, peaked at the largest scale, suggesting that oceanographic processes and climatic gradients may be important. We conclude that formal comparisons of variability across scales nested in contrasting systems are needed, before any generalization on patterns and processes can be made.

Within the COST action EMBOS (European Marine Biodiversity Observatory System) the degree and variation of the diversity and densities of soft-bottom communities from the lower intertidal or the shallow subtidal was measured at 28 marine sites along the European coastline (Baltic, Atlantic, Mediterranean) using jointly agreed and harmonized protocols, tools and indicators. The hypothesis tested was that the diversity for all taxonomic groups would decrease with increasing latitude. The EMBOS system delivered accurate and comparable data on the diversity and densities of the soft sediment macrozoobenthic community over a large-scale gradient along the European coastline. In contrast to general biogeographic theory, species diversity showed no linear relationship with latitude, yet a bell-shaped relation was found. The diversity and densities of benthos were mostly positively correlated with environmental factors such as temperature, salinity, mud and organic matter content in sediment, or wave height, and related with location characteristics such as system type (lagoons, estuaries, open coast) or stratum (intertidal, subtidal). For some relationships, a maximum (e.g. temperature from 15–20°C; mud content of sediment around 40%) or bimodal curve (e.g. salinity) was found. In lagoons the densities were twice higher than in other locations, and at open coasts the diversity was much lower than in other locations. We conclude that latitudinal trends and regional differences in diversity and densities are strongly influenced by, i.e. merely the result of, particular sets and ranges of environmental factors and location characteristics specific to certain areas, such as the Baltic, with typical salinity clines (favouring insects) and the Mediterranean, with higher temperatures (favouring crustaceans). Therefore, eventual trends with latitude are primarily indirect and so can be overcome by local variation of environmental factors.